The invention relates to inhibitors of the glycine cleavage system and their use as potential antipsychotic agents. The invention relates furthermore to a process for treating humans having psychosis, psychosis associated with an illness, schizophrenia, Alzheimers disease or other related psychotic disorders.
Glycine is a neurotransmitter in the central nervous system. There, strychnine sensitive glycine receptors exist, where glycine serves as an inhibitory neurotransmitter. In addition there is a glycine binding site located at the NMDA receptor. Here, glycine serves as a excitatory coagonist. For the full activation of the glycine receptor the presence of glutamate and glycine is mandatory. NMDA Antagonists such as phencyclidine (PCP) and related drugs (e.g. ketamine or dizocilpine) induce symptoms in human volunteers which are not distinguishable from schizophrenia (Luby et al., 1959; Rosenbaum et al., 1959; Bakker and Amini, 1961), i.e. they induce a spectrum of symptoms including the positive, negative and cognitive aspects of schizophrenia (Krystal et al., 1994; Mulhotra et al., 1996). In addition, PCP provokes an exacerbation of symptoms in patients suffering from schizophrenia (Lathi et al., 1995; Malhotra et al., 1997). PCP-induced emotional, cognitive and behavioral changes represent not only a clinical model of schizophrenia (Luby et al., 1962), but moreover PCP-induced behavioral changes in mice and rats mimicking the symptoms of schizophrenia in these model organisms are now frequently used animal models for schizophrenia (e.g. Freed et al., 1984) and have been validated with many antischizophrenic drugs with different mechanisms of action (e.g. Jackson et al., 1993; Gleason et al., 1997; Vanover, 1997; Krebs-Thomson et al., 1998). Amongst these animal models utilizing mice and rats, the most prominent models are PCP-induced hyperlocomotion to model the positive and negative symptoms of schizophrenia and PCP-induced disruption of prepulse inhibition revealing the cognition deficit symptoms of schizophrenia.
Glycine, Glycine (Partial) Agonists and Schizophrenia
Glycine and partial agonists at the glycine site have been evaluated in clinical trials (D""Souza 1995). In particular high doses of glycine gave very promising results (Zylberman 1995 and Heresco-Levy 1999). In two double blind, placebo controlled clinical studies it was shown that 0.4 g/kg and 0.8 g/kg glycine given orally along with their usual antipsychotic medication ameliorated negative symptoms by 15% and 30%, respectively. No changes were observed in side effects.
The effects of D-cycloserine were evaluated in several clinical trial. In one clinical trial doses from 15 to 250 mg/d of D-cycloserine were assessed. The results showed that the dose of 50 mg/d reduced negative symptoms in schizophrenic patients (Goff 1995). In another double blind, placebo-controlled clinical trial it was found that 50 mg/d along with their effective dose of antipsychotics gave an improvement in negative symptoms (Goff 1999).
Glycine and the Glycine Cleavage System
Glycine is not only a neurotransmitter but also one of the major sources of C-1 building blocks. It is catabolized by the Glycine Cleavage System (GCS) to yield carbon dioxide, ammonia and methylene tetrahydrofolate.
The GCS consists of four enzymes:
glycine decarboxylase, P-protein,
hydrogen carrier protein, H-protein
aminomethyltransferase, T-protein,
dihydrolipoamide dehydrogenase, L-protein,
The following reaction scheme applies (Kikuchi 1980): 
In vitro it is possible to substitute the H-protein with lipoic acid (Hiraya 1980).
The invention relates to inhibitors of the glycine cleavage system and their use as potential antipsychotic agents. It could be shown that, for example, valporate and cysteamine are potential inhibitors. The invention relates furthermore to a process for treating humans having psychosis, psychosis associated with an illness, schizophrenia, Alzheimers disease or other related psychotic disorders.
Therefore, it is an object of the invention to provide a process for treating a psychotic disorder in a human patient which comprises administering to said human a sufficient amount of an inhibitor, preferably valporate and/or cysteamine, of the glycine cleavage system.
In detail, the invention provides a process, wherein the psychotic disorder is schizophrenia, major depression, manic-depressive disorder, Alzheimers disease or post-traumatic stress syndrome.
Furthermore, the invention provides a process, wherein administering the glycine cleavage system inhibitor affects augmenting NMDA receptor-mediated neurotransmission.